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L-Type Cav 1.2 Calcium Channel-Α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma

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L-Type Cav 1.2 Calcium Channel-Α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma Published OnlineFirst March 1, 2019; DOI: 10.1158/1078-0432.CCR-18-2146 Translational Cancer Mechanisms and Therapy Clinical Cancer Research L-Type Cav 1.2 Calcium Channel-a-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma Jiu-Yang Zhang1, Pei-Pei Zhang1,Wen-Ping Zhou1, Jia-Yu Yu2, Zhi-Hua Yao1, Jun-Feng Chu1, Shu-Na Yao1, Cheng Wang2, Waseem Lone2, Qing-Xin Xia3, Jie Ma3, Shu-Jun Yang1, Kang-Dong Liu4,5, Zi-Gang Dong4, Yong-Jun Guo3, Lynette M. Smith6, Timothy W. McKeithan7, Wing C. Chan7, Javeed Iqbal2, and Yan-Yan Liu1 Abstract Purpose: One third of patients with diffuse large B-cell an independent prognostic factor for RCHOP resistance after lymphoma (DLBCL) succumb to the disease partly due to adjusting for International Prognostic Index, cell-of-origin rituximab resistance. Rituximab-induced calcium flux is an classification, and MYC/BCL2 double expression. Loss of important inducer of apoptotic cell death, and we investigated CACNA1C expression reduced rituximab-induced apoptosis the potential role of calcium channels in rituximab resistance. and tumor shrinkage. We further demonstrated direct inter- Experimental Design: The distinctive expression of calcium action of CACNA1C with CD20 and its role in CD20 stabi- channel members was compared between patients sensitive lization. Functional modulators of L-type calcium channel and resistant to rituximab, cyclophosphamide, vincristine, showed expected alteration in rituximab-induced apoptosis doxorubicin, prednisone (RCHOP) regimen. The observation and tumor suppression. Furthermore, we demonstrated that was further validated through mechanistic in vitro and in vivo CACNA1C expression was directly regulated by miR-363 studies using cell lines and patient-derived xenograft mouse whose high expression is associated with worse prognosis in models. DLBCL. Results: A significant inverse correlation was observed Conclusions: We identified the role of CACNA1C in ritux- between CACNA1C expression and RCHOP resistance in two imab resistance, and modulating its expression or activity may independent DLBCL cohorts, and CACNA1C expression was alter rituximab sensitivity in DLBCL. Introduction abnormalities, biological features, and prognosis (1, 2). The addition of rituximab, a humanized chimeric anti-CD20 mono- Diffuse large B-cell lymphoma (DLBCL) is the most common clonal antibody, to the standard CHOP chemotherapy (RCHOP) type of non-Hodgkin lymphoma characterized by distinct genetic has significantly improved overall survival (OS) of DLBCL patients (3). However, 30% to 40% of patients experience incom- 1Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou plete response during treatment or progression after the comple- University and Henan Cancer Hospital, Zhengzhou, Henan, China. 2Department tion of RCHOP treatment (4). Salvage therapy and/or autologous of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, stem cell transplantation do not improve the dismal prognosis, Nebraska. 3Department of Molecule and Pathology, Affiliated Cancer Hospital of especially in patients with prior rituximab treatment and early Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China. relapse (5). It is often regarded that rituximab resistance plays a 4China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, China. 5Depart- vital role in treatment failure, thus requires further understand- ment of Pathophysiology, Basic Medical College, Zhengzhou University, fi Zhengzhou, Henan, China. 6Department of Biostatistics, University of Nebraska ings to improve clinical ef cacy of rituximab. Rituximab induces Medical Center, Omaha, Nebraska. 7Department of Pathology, City of Hope cell death via antibody-dependent cell-mediated cytotoxicity National Medical Center, Duarte, California. (ADCC), complement-dependent cytotoxicity (CDC), direct apo- Note: Supplementary data for this article are available at Clinical Cancer ptotic signaling, and possible vaccinal effects (6). It can inhibit the Research Online (http://clincancerres.aacrjournals.org/). expression of the antiapoptotic genes BCL2/BCL-XL by down- – J.-Y. Zhang, P.-P. Zhang, and W.-P. Zhou contributed equally to this article. regulating the survival pathways (refs. 7 9; i.e., p38MAPK, NF-kB, ERK 1/2, and PI3K-AKT). The resistance to rituximab is either Corresponding Authors: Yan-Yan Liu, Affiliated Cancer Hospital of Zhengzhou tumor-intrinsic (i.e., loss of CD20 expression; ref. 10) and/or University, 127 Dong Ming Road, Zhengzhou 450008, Henan, China. Phone: 1008613838176375; Fax: 1008637165588134; E-mail: [email protected]; host-associated factors (FcRIII-a polymorphism at amino acid Javeed Iqbal, Department of Pathology and Microbiology, LTC-11714, Zip 7760, position 158) that inhibit ADCC action (11). Novel anti-CD20 University of Nebraska Medical Center, Omaha, NE 68105. E-mail: [email protected]; antibodies (e.g., Obinutuzumab) have been developed to exceed and Wing C. Chan, City of Hope National Medical Center, Department of Pathology, rituximab action (12, 13), but with limited improvement for Familian Science Building, Room 1215, 1500 East Duarte Rd, Duarte, CA 91010. DLBCL prognosis. E-mail: [email protected]. CD20 belongs to the MS4A gene family, having a tetraspanning doi: 10.1158/1078-0432.CCR-18-2146 membrane structure with an N- and C-terminal cytoplasmic Ó2019 American Association for Cancer Research. domain involved in B-cell proliferation (14). CD20 has been www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst March 1, 2019; DOI: 10.1158/1078-0432.CCR-18-2146 Zhang et al. Table 1. Comparison of clinical characteristics between patients sensitive and Translational Relevance resistant to RCHOP regimen B cells express a wide and diverse pool of ion channels, Resistance Sensitivity Characteristics (n ¼ 43) (n ¼ 68) P value including components of the Cav1 subfamily of voltage-gated Gender L-type calcium channels. L-type calcium channels can be Male, n (%) 20 (47) 32 (47) 0.955 manipulated by many small molecules and are capable of Age, median (range, y) 41 (19–82) 47 (18–80) 0.195 mediating calcium influx, which is required to trigger apopto- Performance status sis. Crosslinking of CD20 molecules by rituximab can induce ECOG score 0–1, n (%) 33 (77) 60 (88) 0.092 calcium influx leading to apoptosis. In this study, we identified Ann Arbor stage n the role of L-type Cav 1.2 Calcium Channel-a-1C (CACNA1C) I/II, (%) 20 (47) 42 (62) 0.115 LDH level in regulating response to rituximab in diffuse large B-cell Normal, n (%) 23 (53) 44 (65) 0.239 lymphoma. These observations provide a rationale that mod- Number of extranodal involvement ulating L-type Cav1.2 calcium channel may increase the clin- More than 1, n (%) 5 (12) 6 (9) 0.630 ical efficacy of rituximab. Actually, more attention has now IPI score been paid to calcium channels due to their involvement in the Low/low-intermediate risk 0–2, n (%) 30 (70) 60 (88) 0.016 proliferation and invasion of cancer cells and their potential Cell origin Germinal-center B cell, n (%) 11 (26) 20 (29) 0.661 modulation by pharmaceuticals. CACNA1C expression, n (%) 19 (44) 52 (76) 0.001 Double expression, n (%) 9 (21) 5 (7) 0.044 considered as a component of a cell-surface calcium channel or as a direct regulator of calcium channel activity (15, 16). Calcium Materials and Methods channels/pumps located in the plasma membrane and subcellu- Patients and cell lines lar organelles can modulate intracellular calcium signaling. Cross- The study was carried out in a retrospective series of 48 DLBCL linking of CD20 molecules by rituximab induces a redistribution cases with cryopreserved tissues and 63 cases with formalin-fixed of CD20 molecules to lipid rafts at the plasma membrane and paraffin-embedded tissues. Basic clinical characteristics of calcium influx leading to apoptosis (17). The increased intracel- patients are presented in Table 1. The diagnosis of DLBCL was lular calcium induced by rituximab was demonstrated to depend confirmed by at least two pathologists in accordance to the World on the calcium channel at the plasma membrane, rather than Health Organization classification (25). All patients were treated those at the endoplasmic reticulum (18). CD20 deficiency sig- with the RCHOP regimen, and involved-field radiotherapy was nificantly reduced ligation-induced intracellular calcium performed as consolidation treatment in 5 cases in the primary responses (19). However, CD20-deficient B cells presented therapy. Responses to treatment were evaluated by CT scans or incomplete blockade of calcium responses (14), which reflect the PET/CT following the response criteria for lymphoma as defined possibility that other calcium channels may participate in regu- by Cheson and colleagues (26). The study was reviewed and lating calcium influx. approved by hospital review boards with informed consent of B lymphocytes express a wide and diverse pool of ion channels, the patients and was conducted in accordance with the Declara- including components of the Cav1 subfamily of voltage-gated tion of Helsinki. Another independent DLBCL cohort (27) was L-type calcium channels (VGCC) which are signature molecules of used to validate the findings. excitable cells (20, 21). L-type calcium channels are composed of OCI-ly7, OCI-ly8, and OCI-ly3 DLBCL cell lines were cultured five subunits, including a1, a2/d, b, and g. There are four different in IMDM (Gibco)
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